The Role of Rubella in the Etiology of Supravalvular Aortic Stenosis

The possibility of an etiological relationship between rubella embryopathy and sporadic forms of supravalvular aortic stenosis is considered. A case is presented of a patient with rubella embryopathy and supravalvular aortic stenosis associated with pulmonary valvular and peripheral pulmonary artery stenosis, bicuspid aortic valve, aortic valve stenosis and subendothelial myocardial fibrosis. A review of the literature revealed many clinical and pathological features common to both syndromes. The hypothesis that rubella virus produced germ-cell mutation and subsequent persistence of rubella in the zygote produced further fetal damage is presented to explain these observations.     

Supravalvular aortic stenosis and total occlusion of the brachiocephalic trunk

In a 4-year-old girl supravalvular aortic stenosis was diagnosed by echocardiography. Her younger brother was operated on for the same heart disease one year before.     

Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome

Williams-Beuren syndrome (WBS), due to a contiguous gene deletion of approximately 1.5 Mb at 7q11.23, is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS) and a specific cognitive phenotype. Large repeats containing genes and pseudogenes flank the deletion breakpoints, and the mutation mechanism commonly appears to be unequal meiotic crossover. Except for elastin, hemizygosity of which is associated with supravalvular aortic stenosis, it is unknown which of the 18 genes in the deletion area contributes to the phenotype. Here, we report the identification and characterization of two novel genes, WBSCR20 and WBSCR22, which map to the common WBS deletion region. WBSCR22 encodes a putative methyltransferase protein strongly expressed in heart, skeletal muscle and kidney. WBSCR20 encodes a novel protein expressed in skeletal muscle with similarity to p120 (NOL1), a 120-kDa proliferation-associated nucleolar antigen, a member of an evolutionarily conserved protein family. A highly similar putative gene, WBSCR20B, flanks the WBS deletion at the telomeric side. Hemizygous deletion of either of the novel genes might contribute to the growth retardation, the myopathy or the premature aging effects in the pathogenesis of WBS.     

SUPRAVALVULAR PULMONARY STENOSIS IN LEVO TRANSPOSITION AND "SINGLE" VENTRICLE

A case of supravalvular and valvular pulmonary stenosis in an L-transposition of the great arteries and "single" or double inlet left ventricle is described. Supravalvular pulmonary stenosis has not heretofore been reported in transposition of the great arteries. The clinical, hemodynamic and angiographic features are described. Surgical correction has many problems.     

Analytical modeling of the instantaneous maximal transvalvular pressure gradient in aortic stenosis

In presence of aortic stenosis, a jet is produced downstream of the aortic valve annulus during systole. The vena contracta corresponds to the location where the cross-sectional area of the flow jet is minimal. The maximal transvalvular pressure gradient (TPG_max) is the difference between the static pressure in the left ventricle and that in the vena contracta. TPG_max is highly time-dependent over systole and is known to depend upon the transvalvular flow rate, the effective orifice area (EOA) of the aortic valve and the cross-sectional area of the left ventricular outflow tract. However, it is still unclear how these parameters modify the TPG_max waveform. We thus derived an explicit analytical model to describe the instantaneous TPG_max across the aortic valve during systole. This theoretical model was validated with in vivo experiments obtained in 19 pigs with supravalvular aortic stenosis. Instantaneous TPG_max was measured by catheter and its waveform was compared with the one determined from the derived equation. Our results showed a very good concordance between the measured and predicted instantaneous TPG_max. Total relative error and mean absolute error were on average 9.4±4.9% and 2.1±1.1 mmHg, respectively. The analytical model proposed and validated in this study provides new insight into the behaviour of the TPG_max and thus of the aortic pressure at the level of vena contracta. Because the static pressure at the coronary inlet is similar to that at the vena contracta, the proposed equation will permit to further examine the impact of aortic stenosis on coronary blood flow.     

Possible dominant inheritance of the idiopathic hypercalcemic syndrome.

A girl, aged 16 months, with idiopathic hypercalcemia (failure to thrive, characteristic face, supravalvular aortic stenosis) was observed. Her serum calcium level was between 14 and 20 mg/100 ml. Both her father and brother were mentally retarded and had calcium deposits in their corneae. Their serum calcium values were 11.9 and 13.0 mg/100 ml, respectively, with increased urinary output of calcium. The family history is suggestive of autosomal dominant inheritance of the disease.     

Multi-species sequence comparison reveals dynamic evolution of the elastin gene that has involved purifying selection and lineage-specific insertions/deletions

Background  

The elastin gene (ELN) is implicated as a factor in both supravalvular aortic stenosis (SVAS) and Williams Beuren Syndrome (WBS), two diseases involving pronounced complications in mental or physical development. Although the complete spectrum of functional roles of the processed gene product remains to be established, these roles are inferred to be analogous in human and mouse. This view is supported by genomic sequence comparison, in which there are no large-scale differences in the ~1.8 Mb sequence block encompassing the common region deleted in WBS, with the exception of an overall reversed physical orientation between human and mouse.     

Genetic disorders of the elastic fiber system.

Over the last decade, a considerable amount of new information has emerged describing the protein components of elastic fibers. It is now evident that elastic fibers are complex extracellular matrix polymers, composed of at least 19 different proteins that comprise both the microfibrillar and the amorphous components of elastic fibers. Mutations in three of the genes encoding the most abundant of these elastic fiber proteins result in a broad spectrum of elastic tissue phenotypes, ranging from skeletal and skin abnormalities to vascular and ocular defects. The following disorders will be discussed in this review: supravalvular aortic stenosis; Williams-Beuren syndrome; cutis laxa; Marfan syndrome; ectopia lentis; familial thoracic aortic aneurysms and dissections; MASS syndrome; isolated skeletal features of Marfan syndrome; Shprintzen-Goldberg syndrome; and congenital contractural arachnodactyly.     

Elastic fibres in health and disease

Elastic fibres are a major class of extracellular matrix fibres that are abundant in dynamic connective tissues such as arteries, lungs, skin and ligaments. Their structural role is to endow tissues with elastic recoil and resilience. They also act as an important adhesion template for cells, and they regulate growth factor availability. Mutations in major structural components of elastic fibres, especially elastin, fibrillins and fibulin-5, cause severe, often life-threatening, heritable connective tissue diseases such as Marfan syndrome, supravalvular aortic stenosis and cutis laxa. Elastic-fibre function is also frequently compromised in damaged or aged elastic tissues. The ability to regenerate or engineer elastic fibres and tissues remains a significant challenge, requiring improved understanding of the molecular and cellular basis of elastic-fibre biology and pathology, and ability to regulate the spatiotemporal expression and assembly of its molecular components.     

Investigation of deletions at 7q11.23 in 44 patients referred for Williams-Beuren syndrome,using FISH and four DNA polymorphisms

Williams syndrome (WS) is associated with a submicroscopic deletion of the elastin gene (ELN) at 7q11.23. The deletion encompasses closely linked DNA markers. We have investigated 44 patients referred for possible WS using fluorescence in situ hybridization (FISH) analysis with a P1 clone containing an insert from the ELN, as well as performing genotype analysis of patients and parents with four DNA polymorphisms. Twenty-four patients were found to have deletions, 19 of whom were found clinically to have typical WS. The facial features were especially characteristic. None of the patients without detectable deletions was reported to have typical WS features, although one had supravalvular aortic stenosis, hypercalcemia, and mental retardation. No evidence was found in this material for variability of the size of the deletion. Our study supports the usefulness of analysis of ELN deletion in WS patients, both for confirmation of diagnosis and for genetic counselling. Received: 2 August 1996     

COMBINED REPLACEMENT OF THE AORTIC VALVE AND ASCENDING AORTA IN JEHOVAH'S WITNESSES: REPORT OF TWO CASES

Two Jehovah's Witnesses with large ascending thoracic aortic aneurysms and aortic insufficiency secondary to annuloaortic ectasia underwent successful combined replacement of the aortic valve and the ascending aorta. One patient received a composite graft containing an aortic valve prosthesis, which necessitated supravalvular coronary ostia reimplantation; the other patient underwent separate aortic valve and left supracoronary ascending aneurysm replacement, with reimplantation of the right coronary ostium into the graft. No blood or blood derivatives were administered. Both patients had uneventful recoveries and continue to do well. To our knowledge, they represent the first reported cases of successful combined replacement of the aortic valve and ascending aorta in Jehovah's Witnesses.     

Domains in tropoelastin that mediate elastin deposition in vitro and in vivo

Elastic fiber assembly is a complicated process involving multiple different proteins and enzyme activities. However, the specific protein-protein interactions that facilitate elastin polymerization have not been defined. To identify domains in the tropoelastin molecule important for the assembly process, we utilized an in vitro assembly model to map sequences within tropoelastin that facilitate its association with fibrillin-containing microfibrils in the extracellular matrix. Our results show that an essential assembly domain is located in the C-terminal region of the molecule, encoded by exons 29-36. Fine mapping studies using an exon deletion strategy and synthetic peptides identified the hydrophobic sequence in exon 30 as a major functional element in this region and suggested that the assembly process is driven by the propensity of this sequence to form beta-sheet structure. Tropoelastin molecules lacking the C-terminal assembly domain expressed as transgenes in mice did not assemble nor did they interfere with assembly of full-length normal mouse elastin. In addition to providing important information about elastin assembly in general, the results of this study suggest how removal or alteration of the C terminus through stop or frameshift mutations might contribute to the elastin-related diseases supravalvular aortic stenosis and cutis laxa.     

Atypical Deletion in Williams-Beuren Syndrome Critical Region Detected by MLPA in a Patient with Supravalvular Aortic Stenosis and Learning Difficulty

Williams-Beuren syndrome (WBS) is a genetic disease characterized by distinct facial features,short stature,hypotonia,mental retardation,overfriendly and hyper-social behavior,congenital heart disease,infantile hypercalcemia,arterial hypertension and other variable clinical manifestations in organs and systems such as the kidneys,eyes,gastrointestinal and osteoarticular systems (Morris and Mervis,2000).This mental retardation syndrome occurs in 1/20,000 live births (Meyer-Lindenberg et al.,2006).It is caused by a 1.55-1.84 Mb microdeletion in 7q 11.23,a region containing approximately 28genes.Depending on the genes deleted,the phenotypes of WBS patients range from isolated supravalvular aortic stenosis (SVAS) to full expression of the WBS characteristics.Most cases are sporadic (Ewart et al.,1993;Perez Jurado et al.,1996).     

Preventing complicated transseptal puncture with intracardiac echocardiography: case report

Supravalvular mitral stenosis is a rare condition characterized by an abnormal ridge, with one or two orifices, covering and obstructing the mitral valve. Preoperative diagnosis is difficult with transtoracic echo (TTE), angiography and magnetic resonance imaging (MRI). In this case, a 36-year-old male, was admitted to our Heart department: He experienced progressive dyspnea on effort and at rest. Diagnosis was made by transesophageal echocardiography which showed, on apical 4-chamber section, an anulare structure attached since a membrane to the atrial wall anterior mitral valve leaflet and just proximal to the posterior mitral leaflet. Pre-operative identification of the supravalvular mitral ring is the target for obtaining good surgical results. Cineangiography and MRI both failed in reaching this objective, whereas, transesophageal echocardiography is the best method to identify this congenital heart disease. Using TEE the identification is not only possible but also easier.     

Use of a novel acellular xenograft as a patch for aortic annular enlargement during aortic valve replacement

A patient with a history of aortic valve endocarditis and surgical debridement presented with acute congestive heart failure because of severe aortic stenosis. During valve replacement surgery, an aortic annular enlargement was required to overcome a potential patient-prosthesis mismatch. We describe the use of a novel, bioresorbable, acellular xenograft for the enlargement patch. This material is expected to remodel into native patient tissue over time. This case offers an alternative implant for left heart reconstruction using a regenerative patch.     

Balloon aortic valvuloplasty as a bridge to aortic valve replacement in a patient with severe calcific aortic stenosis

This case report describes a patient with severe calcific aortic stenosis who was initially considered inoperable because of a very poor left ventricular function and severe pulmonary hypertension. After balloon aortic valvuloplasty, the clinical and haemodynamic status of the patient improved to such an extent that subsequent aortic valve replacement was considered possible and eventually proved to be successful. Balloon aortic valvuloplasty has value as a potential bridge to aortic valve replacement when the risks for surgery are considered to be too high.     

Myocardial proteome changes in aortic stenosis rats subjected to long-term aerobic exercise

The effects of exercise training (ET) on the heart of aortic stenosis (AS) rats are controversial and the mechanisms involved in alterations induced by ET have been poorly clarified. In this study, we analyzed the myocardial proteome to identify proteins modulated by moderate-intensity aerobic ET in rats with chronic supravalvular AS. Wistar rats were divided into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary aortic stenosis (AS-Sed), and exercised AS (AS-Ex). ET consisted of five treadmill running sessions per week for 16 weeks. Statistical analysis was performed by ANOVA or Kruskal–Wallis and Goodman tests. Results were discussed at a significance level of 5%. At the end of the experiment, AS-Ex rats had higher functional capacity, lower blood lactate concentration, and better cardiac structural and left ventricular (LV) functional parameters than the AS-Sed. Myocardial proteome analysis showed that AS-Sed had higher relative protein abundance related to the glycolytic pathway, oxidative stress, and inflammation, and lower relative protein abundance related to beta-oxidation than C-Sed. AS-Ex had higher abundance of one protein related to mitochondrial biogenesis and lower relative protein abundance associated with oxidative stress and inflammation than AS-Sed. Proteomic data were validated for proteins related to lipid and glycolytic metabolism. Chronic pressure overload changes the abundance of myocardial proteins that are mainly involved in lipid and glycolytic energy metabolism in rats. Moderate-intensity aerobic training attenuates changes in proteins related to oxidative stress and inflammation and increases the COX4I1 protein, related to mitochondrial biogenesis. Protein changes are combined with improved functional capacity, cardiac remodeling, and LV function in AS rats.     

Quality of life among patients with severe aortic stenosis

BackgroundThe disease burden of patients with severe aortic stenosis is not often explored, while the incidence is increasing and many patients who have an indication for aortic valve replacement are not referred for surgery. We studied the quality of life of 191 patients with severe aortic stenosis, hypothesising that symptomatic patients have a far worse quality of life than the general population, which could enforce the indication for surgery.MethodsThe SF-36v2 Health Survey was completed by 191 consecutive patients with symptomatic or asymptomatic severe aortic stenosis.ResultsAsymptomatic patients (n = 59) had health scores comparable with the general Dutch population but symptomatic patients (n = 132) scored significantly lower across different age categories. Physical functioning, general health and vitality were impaired, as well as social functioning and emotional well-being. There was no relation between degree of stenosis and physical or mental health scores.ConclusionsBoth physical and emotional problems have a major impact on normal daily life and social functioning of symptomatic patients with severe aortic stenosis, regardless of age. If the aortic stenosis is above the ‘severe’ threshold, the degree of stenosis does not predict disease burden. These results encourage to reconsider a conservative approach in symptomatic patients with severe aortic stenosis. Using the SF-36v2 Health Survey together with this study, an individual patient’s quality of life profile can be assessed and compared with the patient group or with the general population. This can assist in decision making for the individual patient.     

Respective impacts of aortic stenosis and systemic hypertension on left ventricular hypertrophy

It has been reported that 30-40% of patients with aortic stenosis are hypertensive. In such patients, the left ventricle faces a double (i.e. valvular and vascular) pressure overload, which results in subsequent wall volume hypertrophy. From a clinical standpoint, it is difficult to separate the respective contributions of aortic stenosis and systemic hypertension to left ventricular burden and patient's symptoms and thus to predict whether valve replacement would be beneficial. The objective of this theoretical study was therefore to investigate the relative effects of valvular and vascular afterloads on left ventricular hypertrophy. We used a ventricular-valvular-vascular mathematical model in combination with the Arts' model describing the myofiber stress. Left ventricular wall volume was computed for different aortic blood pressure levels and different degrees of aortic stenosis severity. Our simulations show that the presence of concomitant systemic hypertension has a major influence on the development of left ventricular hypertrophy in patients with aortic stenosis. These results also suggest that mild-to-moderate aortic stenosis has a minor impact on left ventricular wall volume when compared with hypertension. On the other hand, when aortic stenosis is severe, wall volume increases exponentially with increasing aortic stenosis severity and the impact of aortic stenosis on left ventricular hypertrophy becomes highly significant.